NIDDM results from at least two defects, namely reduced insulin secretion from pancreatic beta-cell and resistance to insulin action. At least 25% of the non-diabetic population has insulin resistance in the diabetic range. What distinguishes those who eventually develop diabetes if the failure to overcome the insulin resistance by increasing insulin production and secretion. The nature of the impaired beta-cell function in the majority of cases of NIDDM remains unknown. The Zucker fatty rat has severe insulin resistance and hyperlipemia, but does not develop diabetes. A sub-line derived from these rats, the Zucker diabetic fatty (ZDF) rat has similar insulin resistance but the males develop diabetes due to impaired insulin secretion and in this regard are similar to most humans with NIDDM. The proposed studies will investigate the nature of the beta-cell defect in the ZDF rat model of NIDDM. Preliminary experiments have demonstrated a defect in insulin gene transcription in these animals. The activity of key elements in the insulin promoter will be tested in transfected primary ZDF rat beta-cells. Extracts of nuclear proteins will be screened for alterations in the quantities of transcription factors which are known to be key regulators of the insulin promoter. The effects of free fatty acids on gene expression in the ZDF beta-cell will also be determined. These studies will define the beta-cell defect in the ZDF rat and may help give insight into the defects in insulin production and secretion seen in NIDDM.